6-fluoromethyl-3-oxo-4,6-dienic steroids and process for preparing same



' 3 ,437,657 Cg Patented Apr. 8, 1969 3 437 657 l7m-isopropylidenedioxypregnan 2O one and analogues m thereof which fall within the present invention may like- GFLUOROME)HYL'3'OXG4JGDIENIC STEROIDS wise show progestational activity, anti-inflammatory ac- AND PROCESS FOR PREPARING SAME tivity and anti-endotoxic activtiy. Glucocorticoid activity Bernard Ellis Peter Feather, Hugh MacBr-ide, and Vladrmir Petrow London, England, assignors to The British 5 may be shown by the denvatlves of final l'tnhydroxy Drug Houses Limited pregnan-3,20-dione and 17a,21-dihydroxypreguane-3,11, No Drawing piled 7 9 5 5 514, 7 20-trione and by the 21-acyl and 17,21-diacyl derivatives Claims priority, application Great Britain, Dec. 21, 1964, thereof, and their 16-methyl, 16-halo, 16-methy1ene, 16- 51,946/64 halomethylene and 16-halomethyl derivatives particularly C07C 169/30, 169/34; A61k 17/00 where there is additionally a 9u-fluoro substituent and a U.S. C]. 250239-53 2 Clalms 1,4,6 t i i system present.

.MMWW The present invention provides new 6-fluoromethyl- ABSTRACT OF THE DISCLOSURE I3 E(, ;r1 ()Wl,,-4,6 trienlc sterolds including the partial Formula New 6-fluoromethyl-3-oxo-4,6-dienic steroids of the The invention also provides 6-fiuoromethyl-3-oxo-4,6- pregnane series are disclosed. They are prepared by direct dienic steroids of the androstane, 19-norandrostane and reaction of a corresponding 6-hydroxymethyl-3-oXo-4,6- l9-norpregnane series including the partial Formula I dienic steroid with a fluorinating agent. The compounds below. of the invention may possess progestational, ovulation- The invention further provides 6-fluoromethyl-3-oxoinhibiting, and gonadotrophin-inhibiting properties. 20 4,6-dienic steroids of the pregnane series having the following formulae:

CHzR This invention is for improvements in or relating to organic compounds and has particular reference to steroi- Me I dal compounds containing a fluoromethyl substituent ('H at c5. RH. R1

It is an object of the present invention to provide a Me 5 novel and general process for the preparation of 6-fluoromethyl-3-oxo-4,6-dienic and 6-fiuoromethyl-3-oXo-1,4,6- trienic steroids, including the partial Formula I below.

Many of the 6-fiuoromethyl-3-oxo-4,6-dienic and 6-fluoromethyl-3-oXo-1,4,6-trienic steroids of the present CH F invention possess valuable biological properties. Thus, for Wher 6: example, the derivatives of 17fi-hydroxyandrostane which R is H Me or a halogen atom, fall within the scope of the present invention may possess is H, Me, CN or CHZOH, anabolic, androgemc, gonadotrophin-mhibtlng and claudois H or genie properties. The derivatives of l7u-acyloxypregnan- 00 Me 20-one which fall within the scope of the present inven- Me tion may possess progestational, ovulation-inhibiting and gonadotrophin-inhibiting properties. In conjunction with 40 i an oestrogen such for example as ethynyloestradiol, Me mestranol, 17a-chlorethynyl (17a-bromoethynyl) oestradiol and its 3-methyl and 3,17-dimethyl ether, 17a-trifinoropropynyl oestradiol and its 3-methyl and 3,17-dimethyl ether, l7a-trifiuorovinyl oestradiol and its 3-methyl and 3,17-dimethyl ether, the compounds of the present CHzF invention and in particular 17oc-EICCtOXY-G-fiUOIOIIlfithYl- Where:

pregna-4,6-diene-3,ZO-dione and its l-dehydro derivative and the 16-methylene analogues thereof are of value as oral contraceptives and as anti-tumor agents in experimental assays. In addition, the compounds are of value in veterinary Work for the synchronisation of oestrus and for inhibition of ovulation. Such formulations may be administered as pills, tablets and other standard pharma- CHzR ceutical formulations either in the conventional 20 days/ I month regimens or in sequential or serial regimens. The

progestationally active l7a-acyloxypregnan-20-one derivatives are of value in various gynecological disorders such as dysmenorrhea, in endometriosis, disfuctional uterine bleeding, premenstrual tension syndrome, the 0 postponement of normal menstruation, primary and secondary amenorrhea, sub-fertility and inhibition of lactation, and may be administered in standard pharmaceutical formulations for these purposes. The derivatives of R is H or a lower acyl group containing up to 6 carbon atoms,

R is =CH Me, or a halogen atom or CH.Me or =CHX or CH X where X is a halogen atom where:

where:

R is H or a lower acyl group containing up to 6 carbon atoms,

R is OH, a lower acyloxy group containing up to 6 carbon atoms or a halogen atom,

R' is H, Me, =CH lit-OI'L a halogen atom, or CH X or =CHX where X is a halogen atom,

R is a lower alkyl group containing up to 4 carbon atoms,

R is H, OH, a lower acyloxy group containing up to 6 carbon atoms, or a halogen atom,

R' is H, Me, =CH aOH, a halogen atom, or CH X or =CHX where X is a halogen atom,

Y is H or F.

The invention provides the following new compounds:

17;; acetoxy 6-fluoromethylandrosta-4,6-dien-3-one which has anabolic and androgenic properties.

175 acetoxy-6-fluoromethylandrosta-1,4,6-trien-3-one which has anabolic and androgenic properties.

175 acetoxy 6-fiuorornethy1-19-norandrosta-4,6-dien- 3-one which has claudogenic properties.

17 oz acetoxy-6-fluoromethylpregna-l,4,6-triene-3,20-dione which has progestational, anti-ovulatory and gonadotrophin-inhibiting properties.

170: acetoxy-6-fluoromethyl-16-methylenepregna-4,6- dierte-BJO-dione, which has progestational, anti-endotoxic and anti-ovulatory properties.

17a acetoxy-6-fluoromethyl-16-methylenepregna-1,4,6- triene-3,20-dione which has progestational, anti-endotoxic and anti-ovulatory properties.

21 acetoxy 6-fiuoromethyl-17u-hydroxypregna-4,6- diene-3,l1,20-trione and the n -derivative thereof which have glucocorticoid, anti-inflammatory and anti-endotoxic properties.

21 acetoxy 6-fluoromethyl-11B,l7a-dihydroxypregna- 4,6-diene-3,20-dione and the A -derivative thereof which have glucocorticoid, anti-inflammatory and ant-endotoxic properties.

6 fluorornethyl 16a,l7a-isopropylidenedioxypregna- 4,6-diene-3,20 dione and the Il -derivative thereof which have anti-inflammatory properties.

4 According to the present invention there is provided a process for the preparation of 6-fluoromethyl-3-oxo-4,6- diem'c and 6-fluoro-methyl-3-oxo-1,4,6-trieuic steroids includin g the partial formula where R is H or Me, which process comprises treating a G-hydroxymethyl-3-oxo-4,6-dienic steroid including the partial formula (iHzOH with a fluorinating agent to give the corresponding 6- fluoromethyl-3-oxo-4,6-dienic steroid, and if desired dehydrogenating to give the corresponding 6-fiuoromethyl- 3-oxo-l,4,6-trienic steroid.

Conversion of 6-hydroxymethyl-3-oxo-4,6-dienic steroids into the corresponding 6-fluoromethyl-3-oXo-4,6-dienic steroids may be effected by employing fluorinating agents under carefully regulated conditions. The preferred fluorinatin-g agent is 2-chloro-1,1,Z-trifiuorotriethylamine, but other fiuorinating agents such as sulphur tetrafluoride fall within the purview of the present invention.

In a preferred form of the invention, the 6-hydroxymethyl-3-oxo4,6-dienc steroid (II) in a suitable dry inert organic solvent such for example as diethylene glycol dimethyl ether, or an halogenated hydrocarbon such as methylene dichloride or chloroform, is treated at temperatures preferably in the region of 0 to 25 C. with not less than one molecular proportion of 2-chloro-1,1,2- trifluorotriethylamine. The reaction is generally rapid. It may be allowed to proceed during 30 minutes or longer, after which the product is isolated by techniques wellknown to those skilled in the art, and purified by crystallisation, or by chromatography followed by crystallisation. The 6-lluoromethyl-3-oxo-4,6-dienic steroid so obtained may be converted into the corresponding 6-fiuoromethyl- 3-oxo-1,4,6-trienic steroid by l-dehydrogenation, employing for example 2,3-dichloro-5,6-dicyanobenzoqui none but other dehydrogenating agents such as selenium dioxide fall within the purview of the present invention. In a preferred form of the invention, the 6-fluoromethyl- 3-oxo-4,6-dienic steroid and not less than one molecular proportion of 2,3-dichloro-5,6-dicyanohenzoquinone are heated together in a suitable inert organic solvent, until reaction is complete. Benzene may be employed as organic solvent when, at reflux temperature, reaction is complete generally within 10 to 20 hours. Thereafter, the product is isolated by satndard techniques, and purified to give the required 6-fluoromethyl-3-oxo-1,4,6-trienic steroid.

The 6-hydroxymethyl-3-oxo-4,6-dienic steroids (II) employed as starting materials in the present invention are described in our pending application 457,522 filed May 20, 1965, now issued as Patent No. 3,375,167. They are prepared by dehydrogenation, for example with 2,3- dichloro-S,6-dicyanobenzoquinone in aqueous acetone of 3-alkoxy-6-hydroxymethyl-3,S-dienic steroids which may be additionally substituted by Hydroxyl groups: In various positions in the steroid molecule. In general such hydroxyl groups are preferably protected by acylation. Experimental conditions, however, can generally be so adapted as to avoid reaction of the fluorinating agent with 17a-hydroxy groups in pregnan-ZO-one derivatives and with llB-hydroxy groups.

Acyloxy groups in such positions as 11, 12, 16 (including 16-acyloxymethyl), 14, 15, 17, 18, 19, 20, 21 (including the condensation products of 17a-glycols with carbonyl components).

Carbony groups such for example as carbonyl groups at 11 12, 15, 16, 17, C18 and 20- Carbalkoxy groups at C C C C or in the sidechain.

Cyano groups at C C16, C Alkyl groups in particular Me groups at C C11, C C17, C13, C21 and ethyl at C17.

Alkenyl and alkynyl groups in particular vinyl and allyl, trifiuoropropynyl, tritiuorovinyl, ethynyl, propynyl and chlorethynyl at C Methylene, halomethylene and ethylidene groups at 11 C16 and 17- Groups such as benzylidene at C methylene, haloand carboxy methylene at C15IC17.

Lactone, ether and spiroketal residues: Spirolactone residues such as -O.CO.CH .CH attached to C etheric groups at C and bridging C and C spiroketal moieties such as are present in diosgenone, 20,20- ethylene-dioxy groups, 17,17-ethylene-dioxy groups and similar functional derivatives.

Halogen groups and in particular chlorine and fluorine at C C C and C Halomethyl at C Unsaturated linkages in particular at C C C C16 and 17 20)- Cortical side chains, both acylated, or converted into such protected derivatives as bismethylenedioxy, cycliccarbonates, cyclic acetonides or orthoformates.

Epoxides and halohydrins particularly at C The process of the invention may be applied to the 6 hydroxymethyl 3 oxo-4,6-dienic compounds derived from the following steroids or their acyl derivatives: testosterone and 19-nor derivatives thereof Z-methyltestosterone and 19-nor derivatives thereof 17a-methyltestosterone and 19-nor derivatives thereof 9(11)-dehydro-l7a-methyltestosterone and 19-nor derivatives thereof 17a-propynyltestosterone, 17a-chlorethynyl, 17u-trifiuoropropynyl, 17a-trifiuorovinyl testosterone and 19-nor derivatives thereof 17a-acyloxyprogesterones and 19-nor derivatives thereof 9 1 1 )-dehydro-l7u-acyloxyprogesterones 16-methyl-17a-acyloxyprogesterones, 16-halomethyl-17uacyloxy-progesterones 9 1 1)-dehydro-16-methyl-17a-acyloxyprogesterones 16-methylene-17a-acyloxyprogesterones, 16- halomethylene-l7a-acyloxyprogesterones 9 1 1 )-dehydro-l 6-methylene-17a-acyloxyprogesterones l7a-acyloxy-16-ethylideneprogesterones 16a,17a-dimethylmethylenedioxyprogesterone 9 11)-dehydro-16a,17a-dimethylmethylenedioxyprogesterone cortisone 16-methylcortisone, 16-hal0methy1cortisone and the 21- fluoro derivatives thereof 2l-methylcortisone and the 21-fluoro derivatives thereof 16-methylenecortisone, 16-halomethylenecortisone and the 2l-fluoro derivatives thereof 16u-hydroxy cortisone and the (160:, l7a)-acetonide thereof hydrocortisone 16-methy1hydrocortisone, 16-halomethylhydrocortisone and the 2l-fluoro derivatives thereof 21-methylhydrocortisone and the 21-fluoro derivatives thereof 1 6-methylenehydrocortisone, 16-halomethylenehydrocortisone and the 21-fluoro derivatives thereof 16u-hydroxyhydrocortisone and the (16a,17u)-acetonide thereof 170:,2 l-dihydroxypregna-4,9 (1 1)-diene-3,20-dione 16-methyl-17a,21-dihydroxypregna-4,9(1 1)-diene-3,20-

dione 2 1-methyl-l7a,2 l-dihydroxypregna-4,9 (1 l)-diene-3,20-

dione 16-rnethylene-17a,21-dihydroxypregna-4,9(11)-diene- 3,20-dione 1 6ot-hydroxy, 17a,21-dihydroxypregna-4,9 l l -diene- 3,20-dione and the 16, 17 -acetonide thereof 21-fluoro-16u,17a-dihydroxypregna-4,9( 1 1 -diene-3,20-

dione and the (16,17)-acetonide thereof 21-fll10IO-16ec,17ot-dihYdTOXYpfegIlEl-i-BIlC-Ia,1 1,20-trione and the l6,17)-acetonide thereof 21-fluoro-1 1,16a, l7a-trihydroxypregn-4-ene-3,20-dione and the (16,17)-acetonide thereof 21-hydroxypregna-4,17-dien-3-one 1 1-oxo-21-hydroxypregna-4,17-dien-3-one 1 1,21-dihydroxypregna-4,17-dien-3-one 9 1 1 )dehydro-21-hydroxypregna-4,17-dien-3-one 3-oxopregna-4,l7-dien-2 l-oic acid (esters) 3,1 1-dioxopregna-4, l7-dien-21-oic acid (esters) 1 l-hydroxy-3-oxopregna-4,17-dien-2 l-oic acid (esters) 9 1 1)-dehydro-3-oxopregna-4,17-dien-21-oic acid (esters) 2 l-fiuoro-17wacyloxyprogesterones progesterone 16-methylprogesterone 1 l-oxoprogesterone 9 1 1,) -dehydroprogesterone 2 l-methylprogesterone diosgenone 17a-cyano-17 3-hydroxyandrost-4-en-3-one l6 oz and 3)-hydroxytestosterone and 19-nor derivatives 16-methyl-16,17-dehydroprogesterone 16-cyano-progesterone 16-carbalkoxyprogesterones 1 6-hydroxymethylprogesterone 3-(3-oxo-17fi-hydroxyandrost-4-en-17a-yl) propionic acid 2 l-fiuoroprogesterone testololactone 16-fluoro-corticoids The 9tx-fluoro derivatives of the above ILB-hydroxy and 1 l-oxo-steroids.

Following is a description by way of example of methods of carrying the invention into effect.

Example 1.17u-acetoxy-6-fluoromethyl-l6-methylenepregna-4,6-diene-3,20-dione 17a acetoxy 6 hydroxymethyl 16 methylenepregna-4,6-diene-3,20-dione (3 g.) in chloroform (10 ml.) at 0 C. was treated dropwise with 2-chloro-1,1,2-trifluorotriethylamine (3 g.). After a further 5 minutes at 0 C., the mixture was allowed to stand for 20 minutes at room temperature. chloroform ml.) was added, and the solution washed successively with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and water. The solution was dried, the solvent was removed, and the solid residue leached four times with small quantities of ether. The insoluble fraction was crystallise from acetone to give acetoxy 6 fluoromethyl 16 methylenepregna 4,6 diene 3,20 dione, short needles, M.P. 234 C., (decomp.), --125 (in chloroform) AEtOH 277 my (6, 25,500 @014 NujOl 'max.

1260, 1244, 1040, 965 and 890 cm" Example 2.-17u-acetoxy-6-fluoromethylpregna- 4,6-diene-3,20-dione Me i 170: acetoxy 6 hydroxymethylpregna 4,6 diene- 3,20-dione (370 mg.) in dry chloroform (2 ml.) at room temperature was treated with 2-chloro-1,1,2-trifluorotriethylamine (0.5 g.) added dropwise during 2 minutes. The mixture was allowed to stand for 2 hours, and the product, isolated with ether, was chromatographed on silica gel (20 g.) Material eluted with benzene-ether mixtures (9: 1 to 1:1) was crystallised from ethanol to give 17a-acetoxy- 6 fluoromethylpregna 4,6 diene 3,20 dione, needles, M.P. 200 C., [011 +8.5 (in chloroform),

C014 "max.

1741, 1720, 1676 (inflection), 1669 and 1632, and

C S: "max.

1255, 1245, 1055 and 960 emf- Example 3.--1718-acetoxy-6-fluoromethylandrosta- 4,6-dien-3-one 0 Ac Me CHzF CC1 "max.

xElOH 278 111,. (6, 23,000

max.

1741, 1668, 1633 and C S 2 "max.

1265, 1245 and 1050 emf.

Example 4.17(3-acetoxy-6-fluoromethyl-19- norandrosta-4,6-dien-3-one 0A0 Mei CCh "max.

1513? 278 III (6. 24,300),

1741, 1674 and 1634, and

"max.

1240, 1045, 1020 and 883 cmt Example 5.'2 l-acetoxy-6-fluoron1ethyl- 17 whydroxypregna-4,6-diene-3,1 1,20-trione CHZOAC 21 acetoxy 17a hydroxy 6 hydroxymethylpregna-4,6-diene-3,11,20-trione (0.5 g.) suspended in chloroform (2 ml.) at 0 C., was treated with 2-ch1oro- 1,1,2-trifluorotriethylamine (0.7 g.) added dropwise during 2 minutes. The mixture was allowed to stand for 45 minutes at room temperature, and the product was isolated with chloroform. I twas chromatographed on silica gel (25 g.), elution with benzene-ether (4:1 to 1:1) giving material which was crystallised from ethanol. 21- acetoxy 6 fluoromethyl 17a hydroxypregna 4,6- diene 3,11,20 trione had M.P. 215.5 C., [011 +264 (in chloroform),

270 my. (6, 23,200), vglfif 3592, 1749, 1730, 1711, 1652, 1634 and 1585, and

Nujol "max.

1260, 1240 and 1045 cmf Example 6.21-acetoxy-11B,17u-dihydroxy-6-fiuoromethylpregna-4,6-diene-3,20-dione 0 1V161 OH Eton Mm;

(6, 21,800) [a] -l99 (in chloroform).

Example 7.17,8-acetoxy-6-fluoromethylandrosta 1,4,6-trien-3-one CHgF A solution of the product of Example 3, 17 8-acetoxy- 6-fluoromethylandrosta-4,6-dien-3-0ne (300 mg), and 2,3- dichloro-5,6-dicyano-1,4-benzoquinone (300 mg.) in dry benzene ml.) was heated under reflux for 20 hours. The mixture was poured onto alumina 10 g.), and the product eluted with benzene-ether mixtures (3:1 to 1:1). Crystallisation from ethanol gave 17fl-acetoxy-6-fiuoromethylandrosta-1,4,6-trien-3-one,

(e, 10,500) and 290 my (a, 12,000).

Example 8.6-fluoromethyl-16a,17a-isopropylidenedioxypregna-4,6-diene-3,20-dione CH F Example 9.17a-acetoxy-6-fluoromethyl-16-methylenepregna-1,4,6-triene-3,20-dione A solution of the product of Example 1, 1706-3CCtOXY 6 fluoromethyl-1o-methylenepregna-4,6-diene-3,20-dione (0.5 g.), and 2,3-dich1oro-5,6-dicyano-1,4-benzoquinone (0.5 g.) in dry benzene (10 ml.) was heated under reflux for 20 hours. The mixture was poured onto a column of silica gel (20 g.), and the product eluted with ether. crystallisation from ethanol gave 17a-acetoxy-6-fluoromethyl 16-methylenepregna-1,4,6-triene-3,20-dione, M.P. 229.5 (decomp.),

max.

(e, 10,100) and 290 mu (6, 11,600).

Example 10.Tablets containing 1 mg. of 17a-acetoxy-6- fluoromethyl 16-methylenepregna-4,6 diene-3,20-dione and 0.1 mg. of ethinyloestradiol Mg. acetoxy 6-fluoromethyl-l6-methylenepregna- 4,6-diene-3,20-dione l Ethinyloestradiol 0. 1 Industrial methylated spirit, 66 OP (a sufficient quantity). Lactose 107 Starch 13 Starch paste, 10 percent w./w. (a suflicient quantity). Magnesium stearate 1.3 Starch, suflicient to make 129.6

The ethinyloestradiol is dissolved in a suitable quantity of industrial methylated spirit and the 17a-acetoxy-6 fluoromethyl 16 methylenepregna 4,6-diene-3,20-dione mixed with the solution to form a slurry. After addition of the lactose and initial quantity of starch the whole is thoroughly mixed dry and granulated with suflicient 10 percent starch paste. The resultant granules are tray-dried at 50 C., processed through a No. 20 mesh screen and the lubricant (magnesium stearate) added, together with enough starch to produce the required weight. After thorough blending, tablets each weighing 129.6 mg. are compressed using punches of suitable shape and diameter.

Example l1.O/W emulsified ointment containing 0.25

percent of 21 acetoxy 6 fluoromethyl-17a-hydroxypregna-4,6-diene-3, l 1,20-trione The 2l-acetoxy-fi-fluoremethyl-17a-hydroxypregna-4,6- diene-3,l1,20-trione is reduced to an ultra-fine powder either by processing in a fluid energy mill, mechanical mortar and pestle or other suitable means.

The cetostearyl alcohol and soft white paraifin are melted together at 70 C., and the hot mixture strained into a solution of the glycerin and sodium lauryl sulphate in 65 ml. of purified water, also at 70 C. After addition of the benzyl alcohol, the base is allowed to cool with continuous stirring until it begins to set.

A dispersion of the finely powdered 2l-acetoxy-6- fluoromethyl-l7a-hydroxypregna-4,6-diene-3,11,20 trione is made by wetting it with the polyoxyethylene sorbitan monooleate and the remainder of the water. After the dispersion has been blended with the pre-formed base for 15 minutes, the finished ointment is allowed to set up for 1 hour.

1 1 Example 12.--21-acetoxy-6-fluoromethyl-17a-hydroxypregna-1,4,6-triene-3,11,20-trione CH OAC Me O Q Me CHzF CHaF

X223? 255 mu (6, 10,500) and 290 mu (5, 11,900).

Example 14.6-fluoromethyl-16u,17a-isopropylidenedioxypregna-l,4,6-triene-3,20-dione A solution of the product of Example 8, 6-fluoromethyl 16u,17a isopropylidenedioxypregna-4,6-diene-3- 20-dione (0.4 g.), and 2,3-dichloro-5,6-dicyanol,4- benzoquinone (0.4 g.) in dry benzene (10 ml.) was heated under reflux for 18 hours. The mixture was poured onto a column of alumina (10 g.), and the product eluted with benzene-ether mixtures (3:1 to 1:1). Crystallisatiou 12 from ethanol gave 6-fluoromethyl-16a,17 x-isopropylidenedioxypregna-1,4,6-triene-3,20-dione hit? 254 m (6, 10,400) and 289 m (6, 11,600).

Example 15.21-acetoxy-11B,17a-dihydroxy-6-fluoromethylpregna-1,4,6-triene-3,20-dione CHzOAG CH F A solution of the product of Example 6, 21-acetoxy- 115,170; dihydroxy-6-fluoromethylpregna-4,6-diene-3,20- dione (0.5 g.) and 2,3-dichloro-5,6-dicyano-1,4-henzoquinone (0.5 g.) in dry benzene (10 ml.) was heated under reflux for 18 hours. The cooled mixture was washed with dilute aqueous alkali, then with water and dried. It was poured onto a column of silica gel (18 g.), and the product eluted with benzene-ether mixtures (5:1 to 1:1). crystallisation gave 21-acetoxy 11fl,17ot-dihydroxy-6- fluoromethylpregna-l,4,6-triene-3,20-dione,

A212 255 my.

(6, 10,400) and 290 mu (e, 11,850).

Me to Me i (a) Preparation of 17otethyl-6-formyl-3-methoxypregna- 3,5 dien 20-one.17a-ethyl-3-methoxypregna-3,5-dien- 20-one (Weiss, Schaub, Allen, Poletto, Pidacks, Conrow & Coscia, Tetrahedron, 1964, 20, 357) (18 g.) in ethylene dichloride (150 ml.) was added to the complex prepared at 0 C. from dimethylformamide (18 ml.) in ethylenedichloride (65 m1.) and phosgene (12.5 g.) in ethylene dichloride mL), and the mixture was stirred and allowed to warm to room temperature over 3 hours. The resulting complex was hydrolyzed in aqueous methanol ml., 90%) containing sodium acetate (25 g.) for 10 minutes. The product was isolated with ether and purified from acetone-hexane to give the fi-formyl derivative,

(6, 11,000) and 320 m (6, 15,200).

(b) Preparation of ethyl 6 hydroxymethyl-3- methoxypregna-3,5-dieu-20-one.-The foregoing 6-formyl derivative (5 g.) was added to a stirred suspension of lithium borohydride (0.5 g.) in anhydrous tetrahydrofuran (100 ml.). After 5 minutes, the mixture was poured into water. The product was isolated with ether, and purified from aqueous methanol containing a drop of pyridine to give 17:! ethyl 6-hydroxy1uethyl-3-methoxypregna-3,S dien-ZO-one, A 250 mu (e, 18,300).

(c) Preparation of 170: ethyl-6-hydroxymethylpregna- 4,6-diene-3,20-dione.A solution of 2,3 dichloro 5,6- dicyano-l,4-benzoquinone (0.6 g.) in 7 ml. of 95% aqueous acetone (Le. 95 vols. acetone and vols. water) was added dropwise during two minutes to a stirred solution of the foregoing 6-hydroxymethyl-3-enolether (1 g.) in 100 ml. of 95 aqueous acetone. The mixture was stirred for a further 3 minutes, then filtered through a short column of alumina. Removal of the solvent gave a solid which was purified from aqueous methanol. 17a-ethy1-6- hydroxymethylpregna 4,6 diene-3,20-dione crystallised in needles, A 284 mu (6, 22,300).

(d) \17a-ethyl 6 fluorornethylpregna-4,6-diene-3,20 dione.The foregoing 17a-ethyl-6-hydroxymethylpregna- 4,6-diene-3,20-dione (400 mg.) in dry chloroform (2 m1.) at room temperature was treated with 2-chloro-1,1,2-trifiuorotriethylamine (0.5 g.) added dropwise during 2 minutes. The mixture was allowed to stand for an hour, and the product, isolated with ether, was chromatographed on silica gel (20 g.). Material eluted with benzene-ether mixtures (8:1 to 1:1) was crystallised from ethanol to give 170: ethyl-fi-fiuoromethylpregna 4,6 diene-3,20-dione, x 278 m (5, 24,000).

Example 17 In a similar manner, 6-hydroxymethyl-3-oxo-4,6-dienic derivatives of the other starting materials listed above, prepared, for example, as disclosed in copending Application 457,522 filed May 20, 1965, now issued as Patent No. 3,375,167 or from their 3-en0l ethers by the procedure set forth in Example 16 (a), (b) and (c), are converted to the corresponding 6-fluoromethy1 derivatives. By this procedure there are prepared 117fl-acetoxyand 17 B-hydroxy-Z-methyl-6-fluoromethylandroSta-4,6-diene- 3-one from 17fi-acetoxy-2-methyl-6-hydroxymethylandrosta-4,6-dien-3-one;

17fi-acetoxy and 17B-hydroxy-17a-methyl-6- fluoromethylandrosta-4,6-diene-3-one from 175- acetoxy-17u-methyl-6-hydroxymethyl-androsta-4,6- dien-3-one;

175-acetoxy-17a-methyl-6-fluoromethylandrosta-4,6,9( 1 1) trien-3-one from 17fi-acetoxy-17a-methyl-6-hydroxymethylandrosta-4,6,9 1 1 )-triene-3-one;

17fl-acetoxy-17a-(prop-1-ynyl)-6-fluoromethylandrosta- 4,6-dien-3-one from 17fl-acetoxy-17u-(prop-1-ynyl)- 6-hydroxymethylandrosta-4,6-dien-3-one;

17/8-acetoxy-17a-chlorethynyl-6-fiuoromethylandrosta- 4,6-diene-3-one from 17fi-acetoxy17a-chlorethynyl- -hydroxymethylandrosta-4,6-dien-3-one; 17a-acetoxy-6-fluoromethyl-19-norpregna-4,6-diene- 3,20-dione from 17a-ECBtOXY-6-hYdI'OXYII16thYl-19 norpregna-4,6-diene-3,20-dione; 17x-acetoxy-6-fluoromethylpregna-4,6,9(1 1)-triene- 3,20-dione from 17a-acetoxy-6-hydroxymethylpregna- 4,6,9 1 1 )-triene-3,20-dione; l7a-acet0xy-16a-methyl-6-fiuoromethylpregna-4,6-

diene-3,20-dione from 17a-acetoxy-16a-methyl-6- hydroxyrnethylpregna-4,6-diene-3,20-dione; 17u-acetoxy16-chloromethylene-6-fluoromethylpregna- 4,6-diene3,20-dione from 17a-acetoxy-16- chloromethylene-6-hydroxymethylpregna- 4,6-diene-3,20-dione; 17a-acetoxy-16-methylene-6-fluoromethylpregna- 4,6,9 1 1 )-triene-3,20-dione from 17u-acetoxy- =16-methylene-fi-hydroxymethylpregna-4,6,9 1 1)- triene-3,20-dione; 17a-acetoxy-16-ethylidene-6-fiuoromethylpregna-4,6-

diene-3,20-dione from 17a-acet0xy-16-ethylidene-6- hydroxymethylpregna-4,6-diene-3,20-dione; 21-acetoxy-17a-hydroxy-16a-methyl-6- fluoromethylpregna-4,6-diene-3,11,20-trione from 21- acetoxy-17a-hydroxy-16a-methy1-6- hydroxymethylpregna-4,6-diene-3,1 1,20-trione;

21-fluoro-17a-hydroxy-16mmethyl-6-fiuoromethylpregna- 4, 6-diene-3 1 1,20-trione from 21-fluOI'0-17a-hYdIOXY- 16a-methyl-6-hydroxymethylpregna-4,6-diene- 3,1 1,20-trione; 21-acetoxy-17a-hydroxy-16a-chloro-6-fluoromethylpregna- 4,6-diene-3, 1 1,20-trione from 21-acetoxy-17a-hydroxy- 1Got-chloro-6-hydroxymethylpregna-4,6-diene- 3,1 1,20-trione; 21-acetoxy-17a-hydroxy-16ot-chloromethyl-6- fluoromethylpregnat,6diene-3, 1 1,20-trione from 21-acetoxy-17u-hydroxy-16u-chloromethy1-6- hydroxymethylpregna-4,6-diene,3,1 1,20-trione;

2 1-acetoxy-17a-hydroxy-1 6methylene-6- fiuoromethylpregna-4,6-diene-3,11,20-trione from ZI-acetoxy-l7a-hydroxy-16-rnethylene-6- hydroxymethylpregna4,6-diene-3,1 1,20-trione;

2l-acetoxy-17a-hydroxy-16-chloromethylene-6- fluoromethylpregna-4,6-diene-3,11,20-trione from 21-acetoxy-17a-hydroxy-16-chloromethylene-6- hydroxymethylpregna-4,6-diene-3, 11,20-trione;

21-acetoxy-16a,17a-isopropylidenedioxy-6- fluoromethylpregnai,6-diene-3, 1 1,20 trione from 2l-acetoxy-16a,17a-isopropylidenedioxy-6- hydroxymethylpregna-4,6-diene-3,11,20-trione;

21-acetoxy-l 1/3,17a-dihydroxy-9u-fluoro-6- fluoromethylpregna-4,6-diene-3,20-dione from 21-acetoxy-11B,17a-dihydroxy-9'a-fiuoro-6- hydroxymethylpregnai,6-diene-3,20-dione;

21-acetoxy-1 1B, 17a-dihydroxy- 1 6-methyl-6- fluoromethylpregna-4,6-diene-3,20-dione from 21- acetoxy-l1/3,17 x-dihydroxy-16-methyl-6- hydroxymethylpregna-4,6-diene-3,20 dione;

21-acetoxy-11,8,17a-dihydroxyel6-rnethylene-6- fluoromethylpregna-4,6-diene-3,20-dione from 21- acetoxy-l 15,17u-dihydroxy-l6-methylene-6- hydroxymethylpregna-4,6-diene-3,20-dione;

21-acetoxy-1lfi-hydroxy-l6a,17a-isopropylidenedioxy-6- fluoromethylpregna-4,6-diene-3,ZO-dione from 21- acetoxy-l lfi-hydroxy-16a,17a-isopropylidenedioxy-6- hydroxymethylpregna-4,6-diene-3,20-dione;

21-acetoxy-11,8-hydroxy-9u-fluoro-16u,17a-

isopropylidenedioxy-6-fluoromethylpregna-4,6-diene- 3 ,20-dione from 21-acetoxy-1 1fi-hydroxy-9u-fluoro- 16a,17a-isopropylidenedioxy-6-hydroxymethylpregna- 4,6-diene-3,20-dione;

21-acetoxy-.1 7a-hydroxy-6-fluoromethylpregna-4, 6,9(1 1)- triene-3,20-dione from 21-acet0xy-17a-hydroxy-6- hydroxymethylpregna-4,6,9 1 1 -tn'ene-3,20-dione;

21-fluoro-16a,17a-isopropylidenedioxy-6- fluoromethylpregna-4,6,9( 1'1 )-triene-3,20-dione from ZI-fluoro-16oz,17u-isopropylidenedioxy-fihydroxymethylpregna-4,6,9 1 1 )-triene-3,20-dione;

21-1111010-11 3-hydI0Xy-16oz,17oc-iSOpI'OpYlidfiIlGdiOXY-G- fluoromethylpregna-4,6-diene-3,20-dione from 21- fluoro-l1b-hydroxy-16a,17a-isopropylidenedioxy-6- hydroxymethylpregna-4,6-diene-3,20-dione;

21-acetoxy-6-fluoromethy1pregna-4,6,17 (20) -triene 3,11-dione from 21-acetoxy-6-hydroxymethylpregna- 4,6,17 20) -triene-3,1 l-dione;

3,1 1-dioxo-6-fluoromethylpregna-4,6, 17-trien-2 l-oic acid ethyl ester from 3,11-diox0-6-hydroxymethylpregna- 4,6,17-trien-21-oic acid ethyl ester;

21-fluoro-17a-acetoxy-6-fluoromethylpregna-4,6-diene- 3 ,20-dione from 21-fluoro-17a-acetoxy-6- hydroxymethylpregna-4,6-diene-3,2'0di0ne;

6-fluoromethylpregna-4,6-diene-3,20-dione from 6- hydroxymethylpregna-4,6-diene-3,20-dione;

6-fluoromethylpregna-4,6-diene-3,11,20-trione from 6- hydroxymethylpregna-4,6-diene-3,1 1,20-trione;

16a, 17,8-diacetoxy-6-fluoromethylandrosta-4,6-dien-3- one from 16a-17B-diacetoxy-6-hydroxymethylandrosta- 4,6-dien-3-one;

16-methy1-6-fluoromethylpregna-4,6,16-triene-3,20-dione from 1 6-methy1-6-hydroxymethylpregna-4, 6, 1 6- triene-3,20-di0ne; 

